Proinflammatory clearance of apoptotic neutrophils induces an IL-12(low)IL-10(high) regulatory phenotype in macrophages

J Immunol. 2010 Aug 15;185(4):2044-50. doi: 10.4049/jimmunol.1000017. Epub 2010 Jul 21.

Abstract

Clearance of apoptotic exudate neutrophils (efferocytosis) induces either pro- or anti-inflammatory responses in mouse macrophages depending on host genetic background. In this study, we investigated whether neutrophil efferocytosis induces a stable macrophage phenotype that could be recalled by late restimulation with LPS. Bone marrow-derived macrophages previously stimulated by pro- but not anti-inflammatory neutrophil efferocytosis expressed a regulatory/M2b phenotype characterized by low IL-12 and high IL-10 production following restimulation, increased expression of LIGHT/TNF superfamily 14, Th2-biased T cell responses, and permissive replication of Leishmania major. Induction of regulatory/M2b macrophages required neutrophil elastase activity and was partially dependent on TLR4 signaling. These results suggested that macrophage differentiation to a regulatory phenotype plays a role in resolution of inflammation but could contribute to increased humoral Ab responses and parasite persistence in the infected host.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / immunology
  • Cells, Cultured
  • Inflammation / immunology
  • Interferon-gamma / immunology
  • Interferon-gamma / pharmacology
  • Interleukin-10 / metabolism*
  • Interleukin-12 / metabolism*
  • Leishmania major / immunology
  • Leishmaniasis, Cutaneous / immunology
  • Leishmaniasis, Cutaneous / parasitology
  • Leukocyte Elastase / metabolism
  • Lipopolysaccharides / immunology
  • Lipopolysaccharides / pharmacology
  • Macrophages / immunology*
  • Macrophages / metabolism
  • Macrophages / parasitology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred Strains
  • Neutrophils / cytology
  • Neutrophils / immunology*
  • Nitric Oxide / metabolism
  • Phagocytosis / drug effects
  • Phagocytosis / immunology*
  • Th2 Cells / immunology
  • Th2 Cells / metabolism
  • Toll-Like Receptor 4 / metabolism

Substances

  • Lipopolysaccharides
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • Interleukin-10
  • Interleukin-12
  • Nitric Oxide
  • Interferon-gamma
  • Leukocyte Elastase